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PURPOSE: The link between sleep duration and lung cancer risk has been suggested by some epidemiological studies. This meta-analysis was performed to further understand this relationship. METHODS: MEDLINE and EMBASE entries up to December 2022 were searched for eligible publications. A random effects model was used to calculate pooled relative risks (RRs) with 95% confidence intervals (95% CIs). Publication bias was estimated using Begg's and Egger's regression asymmetry test. RESULTS: The meta-analysis included 11 studies (including 10 cohort studies and 1 case-control study). The pooled adjusted RRs were 1.13 (95% CI: 1.03-1.24) for short sleep duration and 1.21 (95% CI: 1.07-1.37) for long sleep duration. CONCLUSION: The findings of this meta-analysis suggested that both short and long sleep duration are associated with an increase in lung cancer risk. These findings need to be corroborated through large-scale prospective studies.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/epidemiologia , Estudos Prospectivos , Duração do Sono , Estudos de Casos e Controles , RiscoRESUMO
BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with poor prognosis and treatment options are scarce. Immunotherapy has shown robust clinical activity in ES-SCLC in previous phase 3 trials. We aimed to assess the efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with standard chemotherapy as a first-line treatment for ES-SCLC. METHODS: The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18-75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1-3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305. FINDINGS: Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9-20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2-17·5]) compared with the placebo group (12·8 months [11·3-13·7]; hazard ratio 0·72 [95% CI 0·58-0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death). INTERPRETATION: Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina , Método Duplo-Cego , Etoposídeo , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
BACKGROUND: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown. METHODS: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values. RESULTS: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy. CONCLUSION: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03668496.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/tratamento farmacológico , Ácidos Nucleicos Livres , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/etiologia , Terapia Combinada , Biologia Computacional/métodos , DNA de Neoplasias , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Estadiamento de Neoplasias , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Malignant tumors are risk factors for a pulmonary embolism (PE), and a PE caused by a tumor is not uncommon. Primary pleural squamous cell carcinoma (PPSCC) is a rare malignancy; thus, a related PE is extremely rare. CASE PRESENTATION: A previously healthy 49-year-old female patient was admitted to Northern Jiangsu People's Hospital owing to chest tightness, cough, and breathing difficulty that persisted for 3 days. Following admission, a computed tomography (CT) pulmonary angiography revealed an embolism in the main pulmonary artery, upper and lower pulmonary artery branch. The patient was treated with alteplase, warfarin, and antibiotics. Over the following year, she experienced recurrent chest pain and tightness and breathing difficulty, with multiple CT pulmonary angiography revealing thrombosis in the right and left main pulmonary artery. No abnormalities were observed in surrogate markers of autoimmune diseases, tumor antigen testing, or ultrasonography; thus, the cause of recurrent PE was not identified. Subsequently, a positron emission tomography-computed tomography (PET-CT) examination revealed diffuse heterogeneous thickening of the right pleura and substantially increased glucose metabolism. A CT-guided pleural biopsy was performed, and histopathological examination of the pleura eventually revealed a diagnosis of PPSCC. CONCLUSIONS: PPSCC is a rare tumor that lacks specific clinical manifestations and is difficult to detect with imaging techniques. The occurrence of PE as the primary manifesting symptom in a patient with PPSCC is extremely rare. Thus, malignant tumors should be considered in patients with no risk factors for PE and/or in those with recurrent PE. An immediate diagnosis and adequate intervention can be achieved with increased awareness of this diagnosis and subsequent related examinations.
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Carcinoma de Células Escamosas/diagnóstico , Pleura/patologia , Neoplasias Pleurais/diagnóstico , Embolia Pulmonar/etiologia , Carcinoma de Células Escamosas/patologia , Dor no Peito/etiologia , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Embolia Pulmonar/diagnóstico por imagemRESUMO
Previous studies have demonstrated that hypoxia can induce phenotypic modulation of pulmonary smooth muscle cells; however, the mechanisms remain unclear. The present study aimed to investigate the effect of the GTPase Rab6A-mediated phenotypic modulation and other activities of rat pulmonary artery smooth muscle cells (RPASMCs). We revealed that Rab6A was induced by hypoxia (1% O2 ) and was involved in a hypoxia-induced phenotypic switch and endoplasmic reticulum stress (ERS) in RPASMCs. After 48 hours of hypoxia, the expression of the phenotype marker protein smooth muscle actin was downregulated and vimentin (VIM) expression was upregulated. Rab6A was upregulated after 48 hours of hypoxia, and the level of glucose-regulated protein, 78 kDa (GRP78) after 12 hours of hypoxic stimulation was also increased. After transfection with a Rab6A short interfering RNA under hypoxic conditions, the expression levels of GRP78 and VIM in RPASMCs were downregulated. Overall, hypoxia-induced RPASMCs to undergo ERS followed by phenotypic transformation. Rab6A is involved in this hypoxia-induced phenotypic modulation and ERS in RPASMCs.
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OBJECTIVE: To explore the impacts of the multidisciplinary team model on the average length of stay and hospital expenses of patients with lung cancer. METHODS: After the multidisciplinary team discussion, 97 patients with lung cancer were selected as the lung cancer group according to the enrollment and elimination criteria the control group was 97 patients with lung cancer managed without team discussion during the same period. All the patients were firstly diagnosed to have lung cancer from December 2011 to December 2013 in Subei People's Hospital. The length of stay, hospital expenses, stages of tumor, types of tumor, Zubrod-ECOG-WHO score, the form of payment, smoking history, sex and age of all the patients were collected. The difference in the average length of stay and hospital expenses between the 2 groups and the associated factors were analyzed by using χ² test, t test and multi-factor stepwise regression analysis. RESULTS: There were 68 males and 29 females with a mean age of (61 ± 9) years in the lung cancer group, while there were 73 males and 24 females with a mean age of (63 ± 10) years in the control group. There were no differences between the 2 groups in tumor staging, tumor types, Zubrod-ECOG-WHO score, the form of payment, smoking history, sex and age (χ² = 4.854, P = 0.563, χ² = 4.248, P = 0.097; χ² = 0.395, P = 0.821; χ² = 1.191, P = 0.554; χ² = 0.108, P = 0.977; χ² = 1.011, P = 0.389; χ² = 0.649, P = 0.519; P = 0.474, P = 0.845, respectively). The average hospital expenses (13 303 vs 16 553, Yuan) were lower and the length of stay (10.33 vs 12.49, days) was shorter in the lung cancer group as compared to the control group (t = 2.616, P = 0.010; t = 2.730, P = 0.007), especially so for the first clinical hospitalization (15 953 vs 19 485 yuan, t = 2.315, P = 0.022; 12.71 vs 14.75 days, t = 1.979, P = 0.049). The average length of stay and the tumor stages were the main factors associated with the average hospital expenses. Except for patients with the limited stage of small cell lung cancer, the average length of stay and hospital expenses showed a tendency to reduce in different stages of the lung cancer group. The hospital cost was lower and the length of stay shorter for patients with stages Ia-IIIa and IIIb-IV in the lung cancer group as compared to the control group (6 722 vs 8 188 yuan; 1.09 vs 2.65 days). CONCLUSIONS: The multidisciplinary team model was an effective measure to cut down the hospital expenses and shorten the length of stay of lung cancer patients, especially for the first hospitalization. Patients may benefit from the multidisciplinary team approach according to their stages. On the basis of reducing the hospital costs and the length of stay, it further reduced the gap of the length of stay and hospital expenses between patients with Ia-IIIa and IIIb-IV diseases, while patients with stage Ia-IIIa disease seemed to benefit more.
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Custos Hospitalares , Tempo de Internação , Neoplasias Pulmonares , Equipe de Assistência ao Paciente , Animais , Estudos de Casos e Controles , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do PulmãoRESUMO
BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.
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Antibacterianos , Infecções Comunitárias Adquiridas , Levofloxacino , Quinolonas , Humanos , Infecções Comunitárias Adquiridas/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Levofloxacino/uso terapêutico , Levofloxacino/efeitos adversos , Levofloxacino/administração & dosagem , Método Duplo-Cego , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Adulto , Idoso , Resultado do Tratamento , Quinolonas/uso terapêutico , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Administração Intravenosa , Infusões Intravenosas , Adulto Jovem , Pneumonia/tratamento farmacológico , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Idoso de 80 Anos ou maisRESUMO
Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .
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BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.
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To date, few studies have investigated whether the RNA-editing enzymes adenosine deaminases acting on RNA (ADARs) influence RNA functioning in lung adenocarcinoma (LUAD). To investigate the role of ADAR in lung cancer, we leveraged the advantages of The Cancer Genome Atlas (TCGA) database, from which we obtained transcriptome data and clinical information from 539 patients with LUAD. First, we compared ARAR expression levels in LUAD tissues with those in normal lung tissues using paired and unpaired analyses. Next, we evaluated the influence of ADARs on multiple prognostic indicators, including overall survival at 1, 3 and 5 years, as well as disease-specific survival and progression-free interval, in patients with LUAD. We also used Kaplan-Meier survival curves to estimate overall survival and Cox regression analysis to assess covariates associated with prognosis. A nomogram was constructed to validate the impact of the ADARs and clinicopathological factors on patient survival probabilities. The volcano plot and heat map revealed the differentially expressed genes associated with ADARs in LUAD. Finally, we examined ADAR expression versus immune cell infiltration in LUAD using Spearman's analysis. Using the Gene Expression Profiling Interactive Analysis (GEPIA2) database, we identified the top 100 genes most significantly correlated with ADAR expression, constructed a protein-protein interaction network and performed a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis on these genes. Our results demonstrate that ADARs are overexpressed in LUAD and correlated with poor patient prognosis. ADARs markedly increase the infiltration of T central memory, T helper 2 and T helper cells, while reducing the infiltration of immature dendritic, dendritic and mast cells. Most immune response markers, including T cells, tumor-associated macrophages, T cell exhaustion, mast cells, macrophages, monocytes and dendritic cells, are closely correlated with ADAR expression in LUAD.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/genética , Interpretação Estatística de Dados , Neoplasias Pulmonares/genética , RNARESUMO
BACKGROUND: Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection. RESEARCH QUESTION: Can TIS effectively reduce sputum P aeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with P aeruginosa infection? STUDY DESIGN AND METHODS: This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300 mg/5 mL twice daily) or normal saline (5 mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28 days on-treatment and 28 days off-treatment. The coprimary end points included changes from baseline in P aeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day 29. RESULTS: The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P aeruginosa density (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; P < .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95% CI, 5.72-10.11; P < .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for P aeruginosa in the tobramycin group than in the placebo group on day 29 (29.3% vs 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups. INTERPRETATION: TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with P aeruginosa infection. TRIAL REGISTRATION: ClinicalTrials.gov; No. NCT03715322; URL: www. CLINICALTRIALS: gov.
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Bronquiectasia , Infecções por Pseudomonas , Humanos , Adulto , Tobramicina , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Antibacterianos/uso terapêutico , Qualidade de Vida , Administração por Inalação , Bronquiectasia/complicações , Bronquiectasia/tratamento farmacológico , Método Duplo-Cego , Pseudomonas aeruginosaRESUMO
This phase I/II trial characterized the tolerability, safety, and antitumor activities of unecritinib, a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1, ALK, and c-MET, in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements. Eligible patients received unecritinib 100, 200, and 300 mg QD, and 200, 250, 300, and 350 mg BID in a 3 + 3 design during dose escalation and 300 and 350 mg BID during expansion. Phase II trial patients received unecritinib 300 mg BID in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) per independent review committee (IRC). Key secondary endpoints included intracranial ORR and safety. The ORR of 36 efficacy evaluable patients in the phase I trial was 63.9% (95% CI 46.2%, 79.2%). In the phase II trial, 111 eligible patients in the main study cohort received unecritinib. The ORR per IRC was 80.2% (95% CI 71.5%, 87.1%) and the median progression-free survival (PFS) per IRC was 16.5 months (95% CI 10.2, 27.0). Additionally, 46.9% of the patients who received recommended phase II dose of 300 mg BID experienced grade 3 or higher treatment-related adverse events. Treatment-related ocular disorders and neurotoxicity occurred in 28.1% and 34.4% of patients, respectively, but none was grade 3 or higher. Unecritinib is efficacious and safe for ROS1 inhibitor-naive patients with ROS1-positive advanced NSCLC, particularly patients with brain metastases at baseline, strongly supporting that unecritinib should become one of the standards of care for ROS1-positive NSCLC.ClinicalTrials.gov identifier: NCT03019276 and NCT03972189.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Progressão da Doença , Proteínas Tirosina QuinasesRESUMO
PURPOSE: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. EXPERIMENTAL DESIGN: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). RESULTS: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. CONCLUSIONS: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Antígeno B7-H1/genética , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/uso terapêutico , Camelus , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Microambiente TumoralRESUMO
OBJECTIVE: To establish a method (negative enrichment by immunomagnetic beads) for detection of tumor cells in pleural effusions and to evaluate the sensitivity and specificity of the method for clinical application. METHODS: Five, 10, 20, 50 and 100 A549 (lung adenocarcinoma) cells were labeled with DAPI and added into 20 ml pleural effusions [containing (1 - 10)×10(6)cells] from heart failure patients, followed by immunomagnetic negative enrichment method. Recovered cancer cells were enumerated using a fluorescent microscope. Tumor cells were enriched from pleural effusion samples by means of density gradient centrifugation and negative enrichment by immunomagnetic beads method, followed by identification with cytology analysis (Wright's Giemsa's staining), immunofluorescence staining (IF) and fluorescence in situ hybridization (FISH) using centromere DNA probes of chromosome 7 and 8. Cytology, IF and FISH evaluations were performed in 53 pleural effusion samples, including 36 cases of malignant disease (25 male and 11 female patients aging 40 to 78 years, mean age (63 ± 9) and 17 cases of benign disease (8 male and 9 female patients aging 25 to 81 years, mean age (53 ± 18). RESULTS: After DAPI staining and mixing with pleural effusions from heart failure patients, the cell recovery rates of A549 cells evaluated under fluorescence microscope were 75%, 78%, 82%, 85%, 88%, and the average recovery rate was 81.6%. Using negative enrichment method and density gradient centrifugation combined with cytology analysis, the positive rates of tumor cells in 36 malignant pleural effusion samples were 81% (29/36) and 61% (22/36), respectively (χ(2) = 4.00, P = 0.039). Using negative enrichment method combined with IF, the positive rate of CK18(+), DAPI(+), CD(45)(-) cells was 100%. Moreover, using negative enrichment method combined with FISH analysis, the positive rate of tumor cells was 86% (31/36), much higher than that using density gradient centrifugation combined with cytology analysis (χ(2) = 5.818, P = 0.012). In 17 cases of benign pleural effusions, using negative enrichment method combined with IF, the positive rate was 100%. But other methods didn't find cancer cells from benign pleural effusions. CONCLUSIONS: It was applicable to enrich tumor cells from pleural effusions using negative enrichment method by immunomagnetic beads. This method combined with cytology analysis or FISH significantly enhanced the sensitivity and specificity of tumor cell detection in pleural effusions. But it was difficult to distinguish cancer cells from mesothelial cells using immunofluorescence staining with CK18, DAPI and CD(45) label. More specific markers were needed to recognize tumor cells from pleural effusions.
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Separação Imunomagnética , Nanopartículas , Derrame Pleural Maligno/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Citodiagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Background: Lung cancer is a common malignant tumor, with, non-small cell lung cancer (NSCLC) accounting for about 80-85% of cases. This study investigated the expression of miR-137 in NSCLC tissues and cells and its effects on the migration and invasion of NSCLC cells and related mechanisms. Methods: We collected the neoplastic and paracancerous tissues of NSCLC patients, detected the expression of miR-137 in NSCLC tissues and cell lines by real-time quantitative polymerase chain reaction (RT-qPCR), and analyzed the correlation between miR-137 expression and the clinicopathological features and survival of NSCLC. Following transfection with miR-137 mimic or inhibitor in NSCLC cell lines (A549 or H1299) to upregulate or downregulate the expression of miR-137, transwell assay was employed to detect the effects of miR-137 on migration or invasion. Online software was employed to predict and analyze the target gene of miR-137, and luciferase reporter gene system was adopted to validate it. The effects of miR-137 on the expressions of COX-2 and Epithelial-Mesenchymal Transition (EMT) related proteins were investigated by Western blot. Results: Compared to paracancerous tissues and BEAS-2B cells, the expressions of miR-137 in NSCLC tissues, A549 and H1299 cells were dramatically down-regulated (P<0.01). After transfection with miR-137 mimic or inhibitor in A549 and H1299 cells, the miR-137 expressions were markedly up-regulated or down-regulated (P<0.01), respectively. The number of migrating or invading cells was observably decreased or increased (P<0.01) after transfected with mimic or inhibitor, respectively, while relative luciferase activity was evidently decreased in cells co-transfected with miR-137 mimic and wild type recombined vector of 3'UTR of COX-2. While the expressions of COX-2 and E-cadherin were both substantially reduced in A549 cells treated with miR-137 mimic, that of vimentin was substantially raised. The expression of miR-137 correlated with smoking history, lymph node metastasis, and TNM clinical stage, and patients with high miR-137 expression had apparent longer survival. Conclusions: The expression of miR-137 was significantly down-regulated in NSCLC tissues and cells, and correlated with NSCLC progress. miR-137 suppressed the migration and invasion of NSCLC cells through regulating EMT relative proteins by targeting COX-2. miR-137 is expected to become a novel biomarker and therapeutic target of NSCLC.
RESUMO
Circular RNAs (circRNAs) are associated with cancer progression. The present study aimed to examine the function of circRNA protein tyrosine phosphatase receptor type A (circRNA_PTPRA) in lung cancer cells and elucidate the underlying molecular mechanisms. The levels of circRNA_PTPRA and microRNA (miRNA/miR)-582-3p were measured in lung cancer tissue and cells using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation and apoptosis were evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. The expression of cyclin D1, caspase-3, and cleaved caspase-3 was assessed via western blotting. The sites of circRNA_PTPRA/miR-582-3p interaction were identified using StarBase, and validated using a dual-luciferase reporter assay. We observed that circRNA_PTPRA levels were remarkably decreased, and miR-582-3p expression was up-regulated in lung cancer tissues and cells. circRNA_PTPRA directly interacts with miR-582-3p and downregulates miR-582-3p expression in lung cancer cells. Moreover, an miR-582-3p inhibitor decreased lung cancer cell proliferation and promoted apoptosis. The overexpression of circRNA_PTPRA decreased cell proliferation and increased apoptotic cell numbers, whereas miR-582-3p overexpression reversed these effects. These findings demonstrate that the up-regulation of circRNA_PTPRA significantly reduces lung cancer cell proliferation and induces apoptosis by regulating miR-582-3p expression.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs , Adenocarcinoma de Pulmão/genética , Apoptose/genética , Caspase 3 , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases , RNA Circular/genéticaRESUMO
INTRODUCTION: Camrelizumab, a humanized immunoglobulin G4-κ monoclonal antibody against programmed cell death protein 1, has exhibited antitumor activity and tolerability across various tumors, including lung cancers. We conducted this double-blind, randomized phase 3 trial to investigate the efficacy and safety of camrelizumab or placebo plus chemotherapy as first-line treatment for patients with advanced squamous NSCLC. The predictive value of circulating tumor DNA (ctDNA) dynamics was also analyzed. METHODS: CameL-sq, a double-blind, randomized phase 3 trial (NCT03668496), was conducted in 53 centers in the People's Republic of China. A total of 389 patients with stage IIIB-IV squamous NSCLC were randomized (1:1) to receive 4 to 6 cycles of carboplatin plus paclitaxel with camrelizumab or placebo (every 3 wk), followed by maintenance therapy with camrelizumab or placebo. Peripheral blood ctDNA samples were collected at baseline and the time after two cycles of treatment. RESULTS: Of 389 eligible patients, 193 patients allocated camrelizumab plus chemotherapy and 196 patients allocated placebo plus chemotherapy were included in the efficacy and safety analysis. The results revealed significantly prolonged progression-free survival (median, 8.5 vs. 4.9 mo; p <0.0001) and overall survival (median, not reached vs. 14.5 mo; p <0.0001) with camrelizumab-chemotherapy versus placebo-chemotherapy. No unexpected treatment immune-related adverse events were observed in both groups. Biomarker analysis revealed that ctDNA clearance after two cycles of treatment was independently associated with dramatically longer progression-free survival (p <0.0001) and overall survival (p <0.0001) in camrelizumab plus chemotherapy group. CONCLUSIONS: Our findings support camrelizumab plus chemotherapy as a first-line treatment option in advanced squamous NSCLC. On-treatment ctDNA dynamics exhibited the potency to predict the efficacy of camrelizumab plus chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Animais , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camelus , Carboplatina , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/patologia , PaclitaxelRESUMO
INTRODUCTION: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation. METHODS: Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review. RESULTS: A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study. CONCLUSIONS: Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB , Humanos , Indóis , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , PirimidinasRESUMO
PURPOSE: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768). METHODS: Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS: A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION: Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Acrilamidas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Receptores ErbB/genética , Éxons , Gefitinibe/uso terapêutico , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Quinazolinas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
BACKGROUND: Previously published studies have shown that circulating tumor cells (CTC) play an important role in clinical staging, efficacy monitoring and prognostic evaluation of lung cancer. The aim of the present study was to investigate the significance of simultaneous in situ detection of multiple tumor marker protein expression and chromosome 8 aneuploid of CTC in the diagnosis and treatment of primary lung cancer. METHODS: We investigated the expression of cytokeratin 18 (CK18) and Vimentin on the surface of CTC and the aneuploidy of chromosome 8 in the peripheral blood of 24 patients with metastatic primary lung cancer, which were detected by subtraction enrichment (SE) and immunofluorescence in situ hybridization (iFISH). Their correlation with clinicopathological features, curative effect, and prognosis was analyzed. RESULTS: The positive rate of CTC was 95.83% (23/24). There was a certain correlation between the positive rate of CTC and smoking, and a correlation between the number of CTC and histopathological type. The number of monoploid, diploid, triploid, and polyploid CTC had no statistical correlation with progression-free survival (PFS) or overall survival (OS). However, a tetraploid CTC count of ≥2 was an unfavorable predictor of response; a tetraploid CTC count ≥1 was an unfavorable prognostic predictor of poor OS. The rate of CK18+ CTC in all 24 patients was 4.35% (1/23). Seven out of these 24 patients were also tested for Vimentin, and the rate of Vimentin+ CTC was 85.71% (6/7). Small-cell (≤5 µm) CTC was found in 6 of these 7 patients and accounted for 11.83% (11/93) of the total CTC. The tumor marker phenotype of small-cell CTC was CK18- and Vimentin+. In addition, circulating tumor microthrombi (CTM) were found in 2 of these 7 patients (28.57%). CONCLUSIONS: SE-iFISH has a high detection rate of CTC in the peripheral blood of patients with metastatic primary lung cancer, and it can identify small cell CTC. Tetraploid CTC count ≥2 can predict poor PFS in patients with advanced lung cancer. Tetraploid CTC count ≥1 could predict poor OS in patients with advanced lung cancer. CTM can predict poor prognosis in patients with lung cancer.